Discovery of VEGFR-2 inhibitors exerting significant anticancer activity against CD44+ and CD133+ cancer stem cells (CSCs): Reversal of TGF-β induced epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma
“…Changes in these markers indicate that KIF2C could promote the invasion and metastasis of HCC cells through EMT. It has been reported that a novel, orally bioavailable compound (VS 8) significantly upregulates E-cadherin and downregulates Vimentin, and that VS 8 promotes apoptosis of HCC cells (49). Moreover, rapamycin was found to effectively reduce the expression of N-cadherin and enhanced the expression of E-cadherin by reducing the expression of BUB1B, therefore inhibiting EMT (37).…”
Background: Hepatocellular carcinoma (HCC) is the leading cause of cancer death. Kinesin family member 2C (KIF2C) has been shown as oncogene in a variety of tumors. However, it's role in HCC remains unclear.Methods: In this study, the expression level of KIF2C in HCC was detected by immunohistochemical staining and RT-PCR, and verified by Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA) and Oncomine database. A curve was established to evaluate the diagnostic efficiency of KIF2C. The effect of KIF2C on HCC was investigated by flow cytometry, Cell Counting Kit-8, Transwell, and the wound-healing assay. We explored the underlying mechanism through epithelial-to-mesenchymal transition (EMT) and transcriptome sequences analysis.Results: KIF2C was overexpression in HCC tissue and related to neoplasm histologic grade (P<0.001), pathology stage (P=0.001), and a dismal prognosis (overall, recurrence-free, and disease-free survival). The diagnostic efficacy of KIF2C was >90% in diagnosing HCC. The HCC cell function experiments showed that KIF2C promoted HCC cell proliferation, migration, invasion, and an accelerated cell cycle, and inhibited apoptosis. Based on western blot analysis and RT-PCR, we found that KIF2C promoted HCC invasion and metastasis through activation of the EMT. Based on transcriptome sequences, we showed that KIF2C promoted HCC through the Ras/MAPK and PI3K/Akt signaling pathway.Conclusions: KIF2C was found to promote the progression of HCC and is anticipated to serve as a biomarker for HCC diagnosis, prognosis, and targeted therapy.
“…Changes in these markers indicate that KIF2C could promote the invasion and metastasis of HCC cells through EMT. It has been reported that a novel, orally bioavailable compound (VS 8) significantly upregulates E-cadherin and downregulates Vimentin, and that VS 8 promotes apoptosis of HCC cells (49). Moreover, rapamycin was found to effectively reduce the expression of N-cadherin and enhanced the expression of E-cadherin by reducing the expression of BUB1B, therefore inhibiting EMT (37).…”
Background: Hepatocellular carcinoma (HCC) is the leading cause of cancer death. Kinesin family member 2C (KIF2C) has been shown as oncogene in a variety of tumors. However, it's role in HCC remains unclear.Methods: In this study, the expression level of KIF2C in HCC was detected by immunohistochemical staining and RT-PCR, and verified by Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA) and Oncomine database. A curve was established to evaluate the diagnostic efficiency of KIF2C. The effect of KIF2C on HCC was investigated by flow cytometry, Cell Counting Kit-8, Transwell, and the wound-healing assay. We explored the underlying mechanism through epithelial-to-mesenchymal transition (EMT) and transcriptome sequences analysis.Results: KIF2C was overexpression in HCC tissue and related to neoplasm histologic grade (P<0.001), pathology stage (P=0.001), and a dismal prognosis (overall, recurrence-free, and disease-free survival). The diagnostic efficacy of KIF2C was >90% in diagnosing HCC. The HCC cell function experiments showed that KIF2C promoted HCC cell proliferation, migration, invasion, and an accelerated cell cycle, and inhibited apoptosis. Based on western blot analysis and RT-PCR, we found that KIF2C promoted HCC invasion and metastasis through activation of the EMT. Based on transcriptome sequences, we showed that KIF2C promoted HCC through the Ras/MAPK and PI3K/Akt signaling pathway.Conclusions: KIF2C was found to promote the progression of HCC and is anticipated to serve as a biomarker for HCC diagnosis, prognosis, and targeted therapy.
“…The abnormal accumulation of ECM triggers the process of fibrosis and immunosuppression by linking SMAD4, BRAF, and TP53 mutations and MYC amplification [ 6 ] and contributes to the cancer-associated fibroblast (CAF) phenotype. Scientists found that inhibiting TGF-β signaling and its downstream signaling pathways could significantly reduce fibrosis [ 66 – 68 ]. Fig.…”
Transforming growth factor β (TGF-β) has long been identified with its intensive involvement in early embryonic development and organogenesis, immune supervision, tissue repair, and adult homeostasis. The role of TGF-β in fibrosis and cancer is complex and sometimes even contradictory, exhibiting either inhibitory or promoting effects depending on the stage of the disease. Under pathological conditions, overexpressed TGF-β causes epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) deposition, cancer-associated fibroblast (CAF) formation, which leads to fibrotic disease, and cancer. Given the critical role of TGF-β and its downstream molecules in the progression of fibrosis and cancers, therapeutics targeting TGF-β signaling appears to be a promising strategy. However, due to potential systemic cytotoxicity, the development of TGF-β therapeutics has lagged. In this review, we summarized the biological process of TGF-β, with its dual role in fibrosis and tumorigenesis, and the clinical application of TGF-β-targeting therapies.
“…10 EMT plasticity of CSCs is identified to be a therapeutic target in HCC. [11][12][13] In a prior work, CSC self-renewal and proliferation are implicated in HCC tumorigenesis. 14 However, the potential mechanism has not been fully elucidated.…”
Background
Hepatocellular carcinoma (HCC) remains a life-threatening malignant tumor. Cancer stem cells (CSCs) harbor tumor-initiating capacity and can be used as a therapeutic target for human malignancies. Bone morphogenetic proteins (BMPs) play a regulatory role in CSCs. This study investigated the role and mechanism of BMP2 in CSCs in HCC.
Methods
BMP2 expression in HCC tissues and cells, and CSCs from HepG2 cells and SMMC7721 cells (HepG2-CSCs and SMMC7721-CSCs) was measured. The association between BMP2 expression and prognosis of HCC patients was analyzed. CSCs were interfered with BMP2 to evaluate the abilities of colony and tumor sphere formation, levels of stemness-related markers, epithelial–mesenchymal transition (EMT), and invasion and migration. Levels of MAPK/ERK pathway-related proteins in HepG2-CSCs were detected after BMP2 knockdown. The effect of the activated MAPK/ERK pathway on HepG2-CSCs was assessed. Finally, the effect of BMP2 inhibition on CSCs in HCC was verified in vivo.
Results
BMP2 showed obvious upregulation in HCC tissues and cells and was further upregulated in CSCs in HCC, with its higher expression indicative of worse prognosis. Silencing BMP2 inhibited colony and tumor sphere formation, levels of stemness-related markers, as well as EMT, invasion and migration of HepG2-CSCs and SMMC7721-CSCs. The MAPK/ERK pathway was suppressed after BMP2 knockdown, and its activation reversed the inhibitory effect of shBMP2 on hepatic CSCs. BMP2 accelerated tumor growth and EMT of CSCs in HCC in vivo.
Conclusion
We concluded that BMP2 knockdown inhibited the EMT, proliferation and invasion of CSCs in HCC, thereby hindering the stemness maintenance via suppressing the MAPK/ERK pathway.
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